Lauri Eklund's research while affiliated with University of Oulu and other places
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Publications (90)
Vascular endothelial (VE)-cadherin in endothelial adherens junctions is an essential component of the vascular barrier, critical for tissue homeostasis and implicated in diseases such as cancer and retinopathies. Inhibitors of Src cytoplasmic tyrosine kinase have been applied to suppress VE-cadherin tyrosine phosphorylation and prevent excessive le...
Purpose:
Defects in the iridocorneal angle tissues, including the trabecular meshwork (TM) and Schlemm's canal (SC), impair aqueous humor flow and increase the intraocular pressure (IOP), eventually resulting in glaucoma. Activation of endothelial tyrosine kinase receptor Tie2 by angiopoietin-1 (Angpt1) has been demonstrated to be essential for SC...
Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC) are widely used in in vitro biomedical research and testing. However, fully matured, adult cardiomyocyte characteristics have not been achieved. To improve the maturity and physiological relevance of hiPSC-derived cardiomyocytes, we co-cultured them with preconstructed vascula...
Dysfunctional and leaky blood vessels resulting from disruption of the endothelial cell (EC) barrier accompanies numerous diseases. The EC barrier is established through endothelial cell tight and adherens junctions. However, the expression patterning and precise contribution of different junctional proteins to the EC barrier is poorly understood....
Vascular endothelial growth factor C (VEGF-C) induces lymphangiogenesis via VEGF receptor-3 (VEGFR3), encoded by the most frequently mutated gene in human primary lymphedema. Angiopoietins (Angs) and their Tie receptors regulate lymphatic vessel development and mutations of the ANGPT2 gene were recently found in human primary lymphedema. However, t...
Hypoxia plays an important regulatory role in the vasculature to adjust blood flow to meet metabolic requirements. At the level of gene transcription, the responses are mediated by hypoxia-inducible factor (HIF) the stability of which is controlled by the HIF prolyl 4-hydroxylase-2 (PHD2). In the lungs hypoxia results in vasoconstriction, however,...
The pathogenesis of numerous diseases is characterised by disruption of the junctions that form the endothelial cell (EC) barrier, the composition of which may differ greatly between organs. However, the expression level variability and precise contribution of different junctional proteins is poorly understood. Here, we focus on organs with continu...
Vascular Endothelial (VE)-cadherin in endothelial adherens junctions is an essential component of the vascular barrier, critical for tissue homeostasis and implicated in progression of diseases such as cancer and eye diseases. Inhibitors of SRC cytoplasmic tyrosine kinase have been applied to suppress tyrosine phosphorylation of VE-cadherin and the...
Endothelial integrity is vital for homeostasis and adjusted to tissue demands. Although fluid uptake by lymphatic capillaries is a critical attribute of the lymphatic vasculature, the barrier function of collecting lymphatic vessels is also important by ensuring efficient fluid drainage as well as lymph node delivery of antigens and immune cells. H...
Endothelial integrity is vital for homeostasis and adjusted to tissue demands. Although fluid uptake by lymphatic capillaries is a critical attribute of the lymphatic vasculature, the barrier function of collecting lymphatic vessels is also important by ensuring efficient fluid drainage as well as lymph node delivery of antigens and immune cells. H...
Endothelial integrity is vital for homeostasis and adjusted to tissue demands. Although fluid uptake by lymphatic capillaries is a critical attribute of the lymphatic vasculature, the barrier function of collecting lymphatic vessels is also important by ensuring efficient fluid drainage as well as lymph node delivery of antigens and immune cells. H...
The maintenance of fluid homeostasis is necessary for function of the neural retina; however, little is known about the significance of potential fluid management mechanisms. Here, we investigated angiopoietin-4 (Angpt4, also known as Ang3), a poorly characterized ligand for endothelial receptor tyrosine kinase Tie2, in mouse retina model. By using...
Increased capillary leakage is a potentially life-threatening condition associated with sepsis and cytokine release syndrome (CRS) that develops as a side effect of novel chimeric antigen receptor (CAR) T-cell cancer immunotherapies. CRS and sepsis are characterized by immune activation, resulting in elevated circulating levels of inflammatory cyto...
Significance
Compromised vascular integrity is associated with capillary leakage in sepsis, but effective therapies stabilizing the vasculature are lacking. Here, we show that targeting β1-integrin in vivo with inhibitory antibodies or deletion of a single allele of endothelial β1-integrin inhibits lipopolysaccharide (LPS)-induced vascular leakage...
Monitoring blood-brain barrier (BBB) opening is of great interest in terms of brain drug delivery in the treatment of brain lymphoma and maybe in the future in other diseases like dementia. A method involving BBB disruption (BBBD) by mannitol infusion has been developed in University of Portland, USA, and then exploited in Oulu University Hospital...
Vascular anomalies are localized defects of morphogenesis that can affect lymphatic and blood vessels. They are generally called birthmarks, typically observed soon after birth and occurring in up to 10% of children. Based on their clinical and histological characteristics, they are classified into vascular tumours and vascular malformations. The m...
The endothelial angiopoietin (ANG)-TIE growth factor receptor pathway regulates vascular permeability and pathological vascular remodelling during inflammation, tumour angiogenesis and metastasis. Drugs that target the ANG-TIE pathway are in clinical development for oncological and ophthalmological applications. The aim is to complement current vas...
Microscopy imaging plays a vital role in understanding many biological processes in development and disease. The recent advances in automation of microscopes and development of methods and markers for live cell imaging has led to rapid growth in the amount of image data being captured. To efficiently and reliably extract useful insights from these...
Rationale: Vascular endothelial growth factor (VEGF) is the main driver of angiogenesis and vascular permeability via VEGF receptor 2 (VEGFR2), while lymphangiogenesis signals are transduced by VEGFC/D via VEGFR3. VEGFR3 also regulates sprouting angiogenesis and blood vessel growth, but to what extent VEGFR3 signaling controls blood vessel permeabi...
Endothelial cells that form the inner layer of blood and lymphatic vessels are important regulators of vascular functions and centrally involved in the pathogenesis of vascular diseases. In addition to the vascular endothelial growth factor (VEGF) receptor pathway, the angiopoietin (Ang)–Tie system is a second endothelial cell specific ligand–recep...
Accurate cell segmentation is vital for the development of reliable microscopy image analysis methods. It is a very challenging problem due to low contrast, weak boundaries, and conjoined and overlapping cells; producing many ambiguous regions, which lower the performance of automated segmentation methods. Cell proposals provide an efficient way of...
Robust cell detection plays a key role in the development of reliable methods for automated analysis of microscopy images. It is a challenging problem due to low contrast, variable fluorescence, weak boundaries, conjoined and overlapping cells, causing most cell detection methods to fail in difficult situations. One approach for overcoming these ch...
Blue Rubber Bleb Nevus syndrome (Bean syndrome, BRBN) is a rare, severe disorder of unknown cause, characterized by numerous cutaneous and internal venous malformations (VMs); gastrointestinal lesions are pathognomonic. We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17 individuals with BRBN. Somatic mutations were also ide...
Summary Impaired angiogenesis has been implicated in adipose tissue dysfunction and the development of obesity and associated metabolic disorders. Here, we report the unexpected finding that vascular endothelial growth factor B (VEGFB) gene transduction into mice inhibits obesity-associated inflammation and improves metabolic health without changes...
Time-lapse microscopy imaging has advanced rapidly in last few decades and is producing large volume of data in cell and developmental biology. This has increased the importance of automated analyses, which depend heavily on cell segmentation and tracking as these are the initial stages when computing most biologically important cell properties. In...
Background: Cancer cell invasion has been traditionally studied in three dimensional (3D) models composed of rat or mouse extracellular matrix (ECM) proteins such as type I collagen and Matrigel. In order to study in vitro 3D oral squamous cell carcinoma (SCC) invasion, our research group developed a human derived myoma organotypic model using uter...
Background:
The composition of the matrix molecules is important in in vitro cell culture experiments of e.g. human cancer invasion and vessel formation. Currently, the mouse Engelbreth-Holm-Swarm (EHS) sarcoma -derived products, such as Matrigel®, are the most commonly used tumor microenvironment (TME) mimicking matrices for experimental studies....
PDF : http://www.cell.com/ajhg/abstract/S0002-9297(15)00456-5#
Somatic mutations in TEK, the gene encoding endothelial cell tyrosine kinase receptor TIE2, cause more than half of sporadically occurring unifocal venous malformations (VMs). Here, we report that somatic mutations in PIK3CA, the gene encoding the catalytic p110α subunit of PI3K, caus...
Background: Cancer cell invasion has been traditionally studied in three-dimensional (3D) models composed of rat or mouse extracellular matrix (ECM) proteins such as type I collagen and Matrigel. In order to study in vitro 3D oral squamous cell carcinoma invasion, our research group developed a human derived myoma organotypic model using uterine le...
Cancer-associated fibroblasts (CAFs) constitute an important part of the tumor microenvironment and promote invasion via paracrine functions and physical impact on the tumor. Although the importance of including CAFs into three-dimensional (3D) cell cultures has been acknowledged, computational support for quantitative live-cell measurements of com...
Venous malformations (VMs) are localized defects in vascular morphogenesis frequently caused by mutations in the gene for the endothelial tyrosine kinase receptor TIE2. Here, we report the analysis of a comprehensive collection of twenty-two TIE2 mutations identified in patients with VM, either as single amino acid substitutions or as double-mutati...
Venous malformations (VMs) are composed of ectatic veins with scarce smooth muscle cell coverage. Activating mutations in the endothelial cell tyrosine kinase receptor TIE2 are a common cause of these lesions. VMs cause deformity, pain, and local intravascular coagulopathy, and they expand with time. Targeted pharmacological therapies are not avail...
Background: Cancer cell invasion has been traditionally studied in three-dimensional (3D) models composed of rat or mouse extracellular matrix (ECM) proteins such as type I collagen and Matrigel. In order to study in vitro 3D oral squamous cell carcinoma invasion, our research group developed a human derived myoma organotypic model using uterine le...
Angiopoietins regulate vascular homeostasis via the endothelial Tie receptor tyrosine kinases. Angiopoietin-1 (Ang1) supports endothelial stabilization via Tie2 activation. Angiopoietin-2 (Ang2) functions as a context-dependent Tie2 agonist/antagonist promoting pathological angiogenesis, vascular permeability and inflammation. Elucidating Ang2-depe...
Automated image analysis is demanded in cell biology and drug development research. The type of microscopy is one of the considerations in the trade-offs between experimental setup, image acquisition speed, molecular labelling, resolution and quality of images. In many cases, phase contrast imaging gets higher weights in this optimization. And it c...
Live cell imaging in 3D platforms is a highly informative approach to visualize cell function and it is becoming more commonly used for understanding cell behavior. Since these experiments typically generate large data sets their analysis manually would be very laborious and error prone. This has led to the necessity of automatic image analysis too...
Angiogenic growth factors have recently been linked to tissue metabolism. We have used genetic gain- and loss-of function models to elucidate the effects and mechanisms of action of vascular endothelial growth factor-B (VEGF-B) in the heart. A cardiomyocyte-specific VEGF-B transgene induced an expanded coronary arterial tree and reprogramming of ca...
The endothelial Tie1 receptor is ligand-less, but interacts with the Tie2 receptor for angiopoietins (Angpt). Angpt2 is expressed in tumor blood vessels, and its blockade inhibits tumor angiogenesis. Here we found that Tie1 deletion from the endothelium of adult mice inhibits tumor angiogenesis and growth by decreasing endothelial cell survival in...
Phase-contrast illumination is simple and most commonly used microscopic method to observe nonstained living cells. Automatic cell segmentation and motion analysis provide tools to analyze single cell motility in large cell populations. However, the challenge is to find a sophisticated method that is sufficiently accurate to generate reliable resul...
Mutations in the endothelial cell tyrosine kinase receptor TIE2 cause inherited and sporadic forms of venous malformation. The recurrent somatic mutation L914F and common germline mutation R849W differ in terms of phosphorylation-level, as well as sub-cellular localization and trafficking of the receptor. Previous studies have shed light on certain...
The angiopoietin (Ang) growth factors and the endothelial Tie receptors regulate blood and lymphatic vessel development, and vascular permeability, inflammation, angiogenic remodeling and tumor vascularization in adult tissues. The angiopoietins activate the Tie receptors in unique in trans complexes at endothelial cell-cell and cell-matrix contact...
The formation of new blood vessels (angiogenesis) is required for the growth of most tumors. The tumor microenvironment also induces lymphangiogenic factors that promote metastatic spread. Anti-angiogenic therapy targets the mechanisms behind the growth of the tumor vasculature. During the past two decades, several strategies targeting blood and ly...
Angiopoietin 1 (Ang1) is an activating ligand for the endothelial receptor tyrosine kinase Tie2, whereas Ang2 acts as a context-dependent agonist or antagonist that has a destabilizing effect on the vasculature. The molecular mechanisms responsible for the versatile functions of Ang2 are poorly understood. We show here that Ang2, but not Ang1, indu...
Angiopoietin-2 (Ang2), a ligand for endothelial TEK (Tie2) tyrosine kinase receptor, is induced in hypoxic endothelial cells of tumors, where it promotes tumor angiogenesis and growth. However, the effects of Ang2 on tumor lymphangiogenesis and metastasis are poorly characterized.
We addressed the effect of Ang2 on tumor progression and metastasis...
Solid tumors require blood vessels for growth and dissemination, and lymphatic vessels as additional conduits for metastatic spread. The identification of growth factor receptor pathways regulating angiogenesis has led to the clinical approval of the first antiangiogenic molecules targeted against the vascular endothelial growth factor (VEGF)-VEGF...
The extracellular matrix (ECM) is a major determinant of the structural integrity and functional properties of the myocardium in common pathological conditions, and changes in vasculature contribute to cardiac dysfunction. Collagen (Col) XV is preferentially expressed in the ECM of cardiac muscle and microvessels.
We aimed to characterize the ECM,...
Germline substitutions in the endothelial cell tyrosine kinase receptor TIE2 (encoded by TEK) cause a rare, inherited form of venous anomaly known as a mucocutaneous venous malformation (VMCM; refs. 1, 2, 3 and V.W., N.L., M.U., A. Irrthum, L.M.B. et al., unpublished data). We identified a somatic 'second hit' causing loss of function of TIE2 in a...
The receptor tyrosine kinase Tie2, and its activating ligand Angiopoietin-1 (Ang1), are required for vascular remodelling and vessel integrity, whereas Ang2 may counteract these functions. However, it is not known how Tie2 transduces these different signals. Here, we show that Ang1 induces unique Tie2 complexes in mobile and confluent endothelial c...
The Tie1 and Tie2 receptor tyrosine kinases and the angiopoietin growth factor ligands, Ang1-4, are essential for vascular
maturation. Targeted deletion of any of the Tie1,Tie2 or Ang1 genes in mice results in embryonic lethality during embryonic days 9.5–13.5. The receptors are expressed mainly in endothelial
cells, while Ang1 is produced by periv...
Angiopoietins are ligands of the Tie2 receptor that control angiogenic remodeling in a context-dependent manner. Tie signaling is involved in multiple steps of the angiogenic remodeling process during development, including destabilization of existing vessels, endothelial cell migration, tube formation and the subsequent stabilization of newly form...
Type XVIII collagen is important in the early phase of retinal vascular development and for the regression of the primary vasculature in the vitreous body after birth. We show here that the retina in Col18a1-/- mice becomes densely vascularized by anomalous anastomoses from the persistent hyaloid vasculature by day 10 after birth. In situ hybridiza...